Spreading implement

ABSTRACT

This invention relates to an implement  1  for applying a volume of liquid to a treatment surface. The implement includes a support means  3  onto which is mounted a receptacle  2 , the receptacle defining a reservoir space  4  which receives the liquid. The receptacle includes a wall  6  having a working surface that is used to spread the liquid over the treatment surface. The wall  6  is resiliently deformable so in use the working surface maintains contact with the treatment surface when spreading the liquid. The implement has a specific application in applying a transdermal lotion to the axilla area of the user. The invention also relates to a system for transdermal administration of a physiological active agent from a liquid composition and a method of conducting the same.

FIELD

This invention relates to an implement for applying a liquid to atreatment surface. The term liquid as used hereinafter in thisspecification is intended to be a reference also to liquid likesubstances such as fluids, lotions, gels, creams or pastes. Theimplement is particularly suitable for applying a topical or transdermalliquid and it has a particular application in applying a medicatedliquid to an area of the body of the user. It will be convenient tohereinafter describe the invention with reference to this particularapplication, however it is to be appreciated that the implement may besuitable for applying liquids to other treatment surfaces

BACKGROUND

Topical liquids such as sunscreens or medicated liquids have previouslybeen provided in squeezable containers or in containers with a fingeroperated pump whereby a portion of the liquid is deposited on thetreatment surface or on a free hand for subsequent application to thetreatment surface. In either case the liquid is spread over thetreatment surface with the free hand which results in the liquid beingapplied to a surface other than the treatment surface. It is not alwaysacceptable for the free hand to be treated with a medicated liquid asthe volume dispensed from the container may be a prescribed dose. Thisis particularly the case where the liquid is intended to have atherapeutic effect at the prescribed dose

It is often desirable to provide an implement which temporarily retainsthe liquid for application to the treatment surface. Implements tend tosuffer from the tension between temporarily retaining the liquid andhaving to release the liquid onto the treatment surface. Implements suchas brushes and sponges are effective in spreading the liquid over thetreatment surface however they tend to retain a volume of residualliquid after the application of the implement to the treatment surface.The retained volume may vary from application to application and as suchit is difficult to accurately apply a metered dose to a treatmentsurface using an implement such as a brush or sponge. Furthermore theimplement can be difficult to clean which can contaminate subsequentliquids particularly if the implement is to be used for a range ofmedicated liquids.

It would be desirable to provide an implement that was capable ofapplying a liquid to a treatment surface while minimising retention ofresidual liquid, and also an implement that was easy to clean after use.

The above discussion of acts, materials, devices, implements and thelike is included in this specification solely for the purpose ofproviding a context for the present invention. It is not suggested orrepresented that any of these matters formed part of the prior art baseor were common general knowledge in the field relevant to the presentinvention as it existed in Australia before the priority date of thisinvention.

SUMMARY

According to one aspect of the invention there is provided an implementfor applying a volume of liquid to a treatment surface including asupport means onto which is mounted, a receptacle defining a reservoirspace which receives the volume of liquid, the receptacle having a baseand a wall, the wall is substantially transverse to the base and has aworking surface that is used to spread the liquid over the treatmentsurface, at least the wall is resiliently deformable so in use theworking surface maintains contact with the treatment surface whenspreading the liquid.

It is preferred that the base is resiliently deformable. It is furtherpreferred that the wall is formed integrally with the base from a thinflexible membrane.

It is preferred that the receptacle includes a hinge formation to allowthe wall to move relative to the base. It is further preferred that thehinge formation is integrally formed with the base and the wall.

It is preferred that the support means is relatively rigid in comparisonto the at least the wall of the receptacle so that at least the wall ismovable relative to the support means when applying the liquid. It isfurther preferred that the support means is releasably attached to thereceptacle. It is further preferred that the wall includes a skirtportion a lower edge of which is attached to the support means. It isalso preferred that the support means is detachably connectable to adispensing means that is operable to dispense the volume of liquid intothe receptacle.

It is preferred that the wall includes an inner portion that is locatedbetween the skirt and the base. It is further preferred that the innerportion extends from the base at an angle greater than or equal to 90°and is continuous from the base to the working surface.

It is preferred that at least the inner portion includes a plurality ofchannels providing a passageway for the liquid from the reservoir spaceto the treatment surface. It is further preferred that the wall iscastellated between the inner portion and the skirt with an exit end ofeach channel spacing each castellation. It is further preferred that theworking surface is limited to the castellation.

It is preferred that the working surface extends along the wall betweenthe inner portion and the skirt. The working surface may extend over theinner portion of the wall and may also extend over the skirt of thewall. It is further preferred that the working surface is substantiallyconvex.

It is preferred that the skirt flares outwardly from the support meanstowards the working surface. Alternatively the skirt is substantiallyparallel to the inner portion.

It is preferred that the treatment surface is the user's skin.

It is further preferred that the treatment surface is the axilla area ofthe users skin.

It will be convenient to hereinafter describe the invention in greaterdetail by reference to the accompanying drawings showing four exampleembodiments of the invention. The particularity of the drawings and therelated detailed description is not to be understood as superseding thegenerality of the preceding broad description of the invention.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is an isometric view of an implement according to a firstpreferred embodiment of the invention.

FIG. 2 is a cross sectional view of the implement from FIG. 1.

FIG. 3 is a detailed view of part of the implement from area A of FIG.2.

FIG. 4 is a detailed view of part of the implement in cross sectionaccording to a second preferred embodiment of the invention.

FIG. 5 is an isometric view of an implement according to a thirdpreferred embodiment of the invention.

FIG. 6 is a cross sectional view of part of the implement from FIG. 5.

FIG. 7 is an isometric view of an implement according to a forthpreferred embodiment of the invention.

FIG. 8 is a front elevation view of the implement from FIG. 1 connectedto a dispensing means.

DETAILED DESCRIPTION

Referring firstly to FIG. 1 which shows a first preferred embodiment ofthe implement 1 which includes a receptacle 2 and a support means 3 forsupporting the receptacle 2. The receptacle 2 defines a reservoir space4 for receiving a volume of liquid. When the implement 1 is in use thereceptacle 2 is brought into engagement with a treatment surface (notshown) so as to enable the liquid to be transferred and spread over atreatment surface by a working surface of the receptacle 2. Thetreatment surface may be any surface however the implement has beendesigned with the intention being that the treatment surface is theuser's skin and in particular the axilla area of the users skin.

Referring now to FIG. 2 which shows the implement 1 in cross section andit can be noted that the receptacle 2 includes a base 5 and a wall 6.The wall includes an inner portion 7 which extends continuously from thebase 5 at an angle thereto towards an upper end 8 of the wall 6. Theangle that the inner portion makes with the base is preferably greaterthan or equal to 90°. FIG. 2 shows the angle of approximately 110°. Askirt portion 9 of the wall extends continuously from the upper end 8 ofthe wall to a lower edge 10 which is attached to the support means 3.FIG. 3 shows more clearly the lower edge of the skirt being formed witha thickened rib 10 which locates in a recess 12 formed on the supportmeans 3. Other means for connecting the receptacle to the support meansare clearly possible however this arrangement allows the receptacle 2 tobe detached from the support means 3 for purposes such as cleaning ofthe receptacle 2.

It is preferred that at least the top end 8 of the wall 6 and base 5 isresiliently deformable in use when contacting the treatment surface. Thewall 6 is preferably formed integrally with the base 5. The portion ofthe wall 6 that engages the treatment surface provides the workingsurface which is used to spread the liquid over the skin. Accordinglythe working surface may extend over the inner portion 7, the upper end 8and/or the skirt portion 9. In the preferred embodiment illustrated inFIGS. 2 and 3 the receptacle 2 is formed from a relatively flexiblemembrane which allows at least the wall 6 to flex acting as a blade-likemember when spreading the liquid across the treatment surface. Therelative flexibility of the membrane allows the wall 6 to roll acrossthe treatment surface spreading the liquid rather than wiping the liquidoff the treatment surface.

In a second preferred embodiment as illustrated in FIG. 4 the receptacle2 is formed with two hinge formations 13. The hinge formation 13 isachieved by a localised reduction of the thickness of the membrane. Thisallows for example for the inner portion 7 of the wall to more easilyflex relative to the base 5 of the receptacle. The hinge formation 13 atthe upper end 8 of the wall allows the inner portion 7 of the wall toflex relatively to the skirt portion 9. This effectively creates a fineredge for the blade-like member.

Referring now to a third preferred embodiment of the receptacle 2 asillustrated in FIGS. 5 and 6 which show the wall 6 being formed withcastellations 14 at the upper end thereof. The castellations 14 are eachspaced by a channel 15 which extends substantially from the base 5towards the upper end of the wall 6. Each channel 15 provides a passageway for the liquid to egress from the reservoir space 4 towards theworking surface. The castellation 14 at the upper end of the wall 6reduces the surface area of the working surface which allows the liquidto be transferred to the treatment surface in a thicker layer. Thechannels 15 are illustrated as extending to the skirt 9 however this isnot essential so long as the channels 15 extend from the reservoir space4 to the working surface of the wall, and that the castellations occupythe working surface.

Referring now to FIG. 7 which shows the fourth preferred embodiment ofthe receptacle 2. In this preferred embodiment the base 5 of thereceptacle 2 is formed with a plurality of dimples 16. The illustrationshows each dimple 16 being in the form of a hexagon however this is notessential. The provision of the dimples 16 makes the receptacle 2 easierto fill in that the liquid is less likely to bounce out of the reservoirspace 4.

Referring now to FIG. 8, it is preferred that the implement 1 bedetachably connectable to a dispensing means 17 or some other portion ofa container 18 that contains a bulk volume of the liquid. Where thedispensing means 17 is in the form of a pump 17 the implement 1 mayengage the pump 17 in such a way as to reduce the exposure of the outletof the pump to air. This will reduce the likelihood that the pumpsuffers from issues such as loss of prime. Furthermore the relativelysolid nature of the support means 3 surrounding the pump 17 will reducethe likelihood of inadvertent discharge from the pump 17.

It will be apparent from the foregoing description that an implement 1incorporating the invention provides an effective and easy to use meansfor applying and spreading liquid over a treatment surface. Theimplement 1 is less likely to retain residual liquid than say a spongeor brush. The castellations 14 with channel 15 formations provides aunique advantage in that the implement can spread a thicker layer ofliquid over the treatment surface.

In one particularly preferred embodiment of the invention the liquidcontained in the container is a transdermal drug delivery composition,particularly a transdermal drug delivery composition of the typedescribed in U.S. Pat. No. 6,299,900 or WO 2006/128255 the contents ofeach of which are herein incorporated by reference. The liquid may andpreferably will be in the form of a gel, cream, foam or viscous solutionwhen delivered to the receptacle.

According to a further aspect of the invention thus provides a systemfor transdermal administration of a physiologically active agent from aliquid composition, the system including

-   -   a container containing the liquid composition including the        physiologically active agent,    -   a dispensing means for delivering liquid from the container; and    -   an applicator for applying the liquid to an area of skin for        transdermal administration said applicator including a        receptacle defining a reservoir space which receives a volume of        liquid from the container, the receptacle having a base and a        wall substantially transverse to the base having a working        surface that is used to spread the liquid over the area of the        skin surface wherein at least the wall is resiliently deformable        so in use the working surface maintains contact with the        treatment surface when spreading the liquid.

The applicator may be removably mountable on the container or containerlid to allow convenient application of liquid to the receptacle andcleaning or replacement.

The liquid will preferably comprise a volatile liquid, a physiologicallyactive agent and preferably a viscosity modifying agent.

The volatile liquid (also sometimes called a “volatile carrier” or“vehicle”) will typically be present in a higher concentration, such as80% or more w/w. The volatile liquid may be any solvent that ispharmacologically suitable and many such solvents are known in the art.One of the advantages of the inclusion of a volatile solvent or volatilecarrier is that it facilitates the composition to dry rapidly, allow theabsorption of the active agent, and avoid the problems of accidentallydosing others by confining administration to a small area of skin,preferably the axilla. Preferably the volatile liquid is a solventhaving a vapour pressure above 35 mm Hg at atmospheric pressure andnormal skin temperature of 32 degrees Celsius. Preferably, the solventis a lower alkyl alcohol or a mixture of such alcohols. Suitablesolvents include ethanol, ethyl acetate, isopropanol, acetone, ethylformate, methyl acetate, methyl ethyl ketone, pentane and chloroform ormixture thereof in the range of about 40 to 99% v/v of the composition,preferably more than 50%, 60%, 70% or 80%. An aerosol propellant, suchas dimethyl ether or R134a, may also constitute a volatile liquid forthe purpose of the present invention.

The composition may include a viscosity modulating agent. The term“viscosity modulating agent” is used to refer to a component of thecomposition which alters the viscosity of the overall resultingcomposition. The nature of the viscosity modulating agent depends notonly on the agent itself, but also the proportion in which it is presentand the presence or absence of other components. For example, a gellingagent may act as a viscosity modulating agent providing that anactivator for that gelling agent is present. For example,hydroxypropylmethylcellulose (HPMC) may be used in a composition with anactivator, in which the volatile solvent is a lower alkyl alcohol at aconcentration of around 2% w/w. A suitable activator would be sodiumchloride. Concentration may be important as, in this example, at 0.1%w/w HPMC has different effects. A thickening agent is one whichincreases viscosity, and is often anhydrous.

The viscosity modulating agent will commonly be a thickening agent or agelling agent. It will often be used to increase the viscosity of thecomposition containing a solution of the physiologically active agent inthe volatile solvent. Given the nature of the volatile solvents, thesolution will typically have very low viscosity. The purpose of theviscosity modulating agent is to increase the viscosity of the solutionsuch that the composition is retained in the vicinity of the area ofapplication for a brief period of time so as to permit increased uptakeof the physiologically active agent at that site. The viscositymodulating agent preferably increases the viscosity to about that of atypical lotion (e.g., sunscreen), but not to the point where thecomposition becomes a gel. Typically, the viscosity of a transdermaldrug delivery composition according to the invention will be less than300 centipoise and often about 150 centipoise.

The viscosity modulating agent must retain its activity in the contextof the other components of the composition of the invention. Inparticular, the thickening agent must remain active and stable in thisenvironment. For example, where the composition has a high alcoholcontent (for example, where the volatile solvent comprises primarilyalcohol at greater than 80% v/v), the thickening agent must be effectivein a high alcoholic environment. Having these requirements in mind, askilled person can select several thickening agents from those known inthe art. Desirably, a thickening agent also inhibits the solventevaporation rate from the composition so as to enhance the so-called“solvent burst” of active agent into the skin at the site ofapplication. In one embodiment the thickening agent includes polyvinylpyrrolidone or PVP (Povidone™).

It will be appreciated by one skilled in the art that the amount ofthickening agent required is a question of degree and compromise withother parameters. It is also known that many thickening agents have peakactivity at a particular concentration, and that activity may drop offsubstantially with slightly higher and slightly lower percentageconcentrations. For example, in one preferred embodiment where thecomposition comprises over 80% alcohol and the thickening agent used isPVP, the desirable concentration of PVP is between 1 and 3%, and itsactivity is substantially reduced outside that range.

Gelling agents are matrix-forming agents which, once activated, act byforming a matrix within and around the composition they are in.Thickening agents are usually anhydrous agents which increase theviscosity of the composition.

The physiologically active agent may be selected from any of the agentsdescribed in U.S. Pat. No. 6,299,900 and WO2006/128255, the contents ofeach of which are herein incorporated by reference. Physiologicallyactive agents that may be used in the system of the present inventioninclude any locally or systemically active agents which can be deliveredthrough the skin to achieve a desired effect. These active agents(grouped by therapeutic class) may include:

-   (a) Alimentary System agents including antidiarrhoeals.-   (b) Cardiovascular System agents including:    -   (i) antihypertensives;    -   (ii) calcium channel blockers;    -   (iii) antiarrhyrthmics;    -   (iv) antiangina agents;    -   (v) beta-adrenergic blocking agents;    -   (vi) cardiotonic glycosides;    -   (vii) adrenergic stimulants;    -   (viii) vasodilators; and    -   (ix) antimigraine preparations.-   (c) Drugs Affecting Blood and Haemopoietic Tissues including:    -   (i) anticoagulants and thrombolytic agents; and    -   (ii) haemostatic agents.-   (d) Drugs Affecting the Central Nervous System including:    -   (i) analgesics;    -   (ii) antipyretics; and    -   (iii) others including acetylsalicylic acid (aspirin),        paracetamol, and phenazone.-   (e) Hypnotics and sedatives.-   (f) Antianxiety agents.-   (g) Neuroleptic and antipsychotic drugs.-   (h) Antidepressants, tetracyclic antidepressants, monoamine oxidase    inhibitors and selective serotonin re-uptake inhibitors.-   (i) CNS stimulants.-   (j) Anti-Alzheimer's agents.-   (k) Antiparkinson agents and dopamine-2 agonists.-   (l) Anticonvulsants.-   (m) Antiemetics, antinauseants and 5HT-3 receptor antagonists.-   (n) Musculoskeletal System including:    -   (i) Non-steroidal anti-inflammatory agents;    -   (ii) Additional non-steroidal antiinflammatory agents;    -   (iii) Antirheumatoid agents;    -   (iv) Muscle relaxants; and    -   (v) Agents used in gout and hyperuricaemia.-   (o) Hormones and Steroids including:    -   (i) oestrogens and derivatives thereof;    -   (ii) progesterone and other progestagens and derivatives        thereof;    -   (iii) antiandrogens;    -   (iv) antioestrogens and derivatives.    -   (v) androgens and anabolic agents and derivatives thereof;    -   (vi) 5-alpha reductase inhibitors;    -   (vii) corticosteroids;    -   (viii) further steroidal antiinflammatory agents;    -   (ix) pituitary hormones and their active derivatives or analogs;    -   (x) thyroid hormones; and    -   (xi) other miscellaneous hormone agents such as octreotide.-   (q) Pituitary inhibitors.-   (r) Ovulation inducers.-   (s) Hypoglycaemic agents.-   (t) Genitourinary System agents.-   (u) Diuretics, related diuretics and loop diuretics.-   (v) Antidiuretics including their active derivatives or analogs.-   (w) Obstetric drugs including agents acting on the uterus.-   (x) Prostaglandins.-   (y) Antimicrobials including:    -   (i) cephalosporins;    -   (ii) penicillins;    -   (iii) tetracyclines and other tetracycline-type antibiotics;    -   (iv) minoglycosides;    -   (v) quinolones.    -   (vi) sulphonamides;    -   (vii) sulphones; and    -   (viii) other miscellaneous antibiotics.-   (z) Antituberculosis drugs.-   (aa) Antimalarials.-   (ab) Antiviral agents.-   (ac) Anthelmintics.-   (ad) Cytotoxic agents.-   (ae) Metabolism agents including anorectic and weight reducing    agents.-   (af) Agents used in hypercalcaemia and their active derivatives or    analogs.-   (ag) Respiratory System agents including:    -   (i) antitussives;    -   (ii) expectorants;    -   (iii) decongestants; and    -   (iv) bronchospasm relaxants and prodrugs and derivatives        thereof.-   (ah) Allergy and Immune System agents including:    -   (i) antihistamines.-   (ai) Local anaesthetics.-   (aj) Stratum corneum lipids.-   (ak) Neuromuscular blocking agents.-   (al) Smoking cessation agents.-   (am) Insecticides and other pesticides which are suitable for local    or systemic application.-   (an) Dermatological agents.-   (ao) Allergens for desensitisation.-   (ap) Nutritional agents.-   (aq) Keratolytics.-   (ar) Psychicenergisers.-   (as) Anti-acne agents.-   (at) Anti-psoriasis agents.-   (au) Anti-itch agents.-   (av) Anticholinergic agents.-   (aw) Other physiologically active peptides and proteins including    small to medium-sized peptides.

It is particularly preferred that the active is effective via thesystemic circulation and still more preferably the active agentcomprises a hormone, particularly selected from the group consisting ofoestrogens, progestins and androgens, including prodrugs and derivativesthereof. Most preferably the active agent comprises testosterone or aderivative or prodrug thereof.

The preferred active agent is testosterone or a derivative thereof,which may be used in the treatment of testosterone deficiency in men andwomen and the conditions and diseases resulting therefrom. Thecomposition may therefore comprise testosterone or a derivative thereof.There are number of closely related androgenic compounds which aresynthetically derivatized from testosterone are known to provide thesame or a similar physiologic activity. Such compounds include withoutlimitation, testosterone salts, such as acetate, enanthate, cypionate,isobutyrate, propionate, undecanoate esters, cyproterone acetate,danazol, finasteride, fluoxymesterone, methyltestosterone, nandrolonedecanoate, nandrolone phenpropionate, oxandrolone, oxymetholone,stanozolol, and testolactone. Contrary to what might be expected fromthe activity of testosterone, the applicant has found that the inventionmay be used to provide rapid delivery of testosterone for transdermaladministration of without inducing unacceptable levels of side effectsthat distress a subject such as sweating and odour, which have beenattributed to the presence of elevated testosterone.

Testosterone production in both men and women declines naturally withage. Testosterone deficiency may result from disease or damage to thehypothalamus, pituitary gland, or testicles that inhibits hormonesecretion and testosterone production, and is also known ashypogonadism. Depending on age, insufficient testosterone production canlead to abnormalities in muscle and bone development, underdevelopedgenitalia, and diminished virility.

Testosterone deficiency in men (hypogonadism) may be present at birth(congenital) or may develop later (acquired). It is classified by thelocation of its cause along the hypothalamic-pituitary-gonadal axis:

Primary, disruption in the testicles

Secondary, disruption in the pituitary

Tertiary, disruption in the hypothalamus.

The most common congenital cause is Klinefelter's syndrome. Thiscondition, which is caused by an extra X chromosome, results ininfertility, sparse facial and body hair, abnormal breast enlargement(gynecomastia), and small testes.

Congenital hormonal disorders such as leutenizing hormone-releasinghormone (LHRH) deficiency and gonadotropin-releasing hormone (GnRH)deficiency (e.g., Kallmann's syndrome) also may cause testosteronedeficiency.

Other congenital causes include absence of the testes (anorchism; alsomay be acquired) and failure of the testicles to descend into thescrotum (cryptorchidism).

Acquired causes of testosterone deficiency include chemotherapy; damageoccurring during surgery involving the pituitary gland, hypothalamus, ortestes; glandular malformation; head trauma that affects thehypothalamus; infection (e.g., meningitis, syphilis, mumps); isolated LHdeficiency (e.g., fertile eunuch syndrome); radiation; testiculartrauma; and tumors of the pituitary gland, hypothalamus, or testicles.

Androgen deficiency in women has been associated with an increased rateof sexual problems or complaints in a number of studies. These problemsare frequently encountered in oophorectomized women and those withandrogen deficiency from other causes. Hypoactive sexual desire disorder(HSDD) in women is the persistent or recurring deficiency (or absence)of sexual fantasies, thoughts and/or desire for, or receptivity to,sexual activity, which causes personal distress. The cause may be eitherphysiological or psychological or a combination of both. Commonphysiological etiologies include hormone deficiencies, medications, andsurgical interventions. Any disruption of the female hormonal milieucaused by these etiologies can result in decreased sexual desire. Thelack of, or a decrease in, sexual desire may also be secondary to poorsexual arousal and response, or to pain associated with sexual activity.Another factor may be difficulty with inability to attain or maintainsufficient sexual excitement, a condition known as female sexual arousaldisorder (FSAD).

The invention may be used in the treatment of sexual dysfunction in menand women.

Normal daily production of testosterone in normal young men ranges from3-10 mg per day with diurnal variation (maximum ˜7 am decliningthroughout the day). The aim of testosterone therapy in men is todeliver physiologic amounts of testosterone to the systemic circulationproducing serum testosterone levels within the normal range for healthymen (e.g. 300-1000 ng/dL or 10-35 nM).

Several clinical studies have demonstrated that in conditions such asfemale sexual dysfunction, testosterone administration, which is aimedat restoring testosterone levels to normal reproductive levels, iseffective in improving sexual function. The studies to date suggest thatsystemic administration of doses ranging from 150 μg to 300 μg a daywould be sufficient to return testosterone levels to mid- to highpremenopausal levels in androgen deficient women.

In one embodiment, the invention is used to deliver a compositioncontaining testosterone as the active agent to the axilla of a patientto result in a blood level of testosterone of at least a predeterminedamount. In one embodiment, the predetermined amount is the normal range.In the case of testosterone, the blood level achieved is at least 200ng/dL, preferably 300-1000 ng/d L.

The invention may be used in the treatment of a wide variety ofconditions responsive to testosterone therapy such as AIDS WastingSyndrome, micropenis, somatopause, andropause, viropause, or androgendeficiency in adult males (ADAM), anemia from renal dialysis or chronickidney disease, benign prostatic hyperplasia, acne, diabetes,infertility, periodontal disease, post anabolic steroid abuse, dry eyes,diabetic retinopathy, retinopathy, and Lupus Erythematosis decreasedbone density (i.e. osteoporosis), hyperlipemia, predisposition towardprostrate cancer, heart disease, angina, and hypertension.

In further embodiments, the invention may be used in a method oftreatment of oestrogen and/or progestin deficiency, a method oftreatment of chronic pain, and a method of treatment of anxiety relateddisorders.

The composition may have antiperspirant and/or deodorant properties. Thecomposition therefore allows the active agent to be rapidly deliveredfor transdermal administration whilst also enabling perspiration and/orodour to be reduced. The invention facilitates delivery of thecomposition to areas such as the axilla for transdermal drug deliverywithout patient inconvenience of not using normalantiperspirant/deodorant products (important for patient compliance)which may otherwise interfere with delivery of the active.

The antiperspirant and/or deodorant properties of the composition areparticularly advantageous when the physiologically active agent istestosterone or derivatives thereof for treating testosterone deficiencyin a subject. Testosterone is responsible for increasing perspirationand producing perspiration and perspiration related odour in thepresence of 5-alpha-reductase, due to the conversion of testosterone todihydrotestosterone (DHT).

In one embodiment, the thickening agent may be an antiperspirant and/oran occlusive agent for the drug delivery composition. In anotherembodiment, both a deodorant and an antiperspirant are in a compositionwith the at least one active agent and a dermal penetration enhancer.Suitable thickening agents include polyvinyl pyrrolidone or PVP(Povidone™). The antiperspirant may be an occlusive agent also, and athickening, occlusive agent may have antiperspirant effects.

In some embodiments, the thickening agent is an antiperspirant or thecomposition further includes an antiperspirant and/or a deodorant.

Despite the inherent antiperspirant and/or deodorant properties of thecomposition, the composition may be optionally administered withdeodorant and antiperspirant additives that do not interfere with theactive. In another form, the liquid may comprise at least onephysiologically active agent; and at least one volatile solvent; and atleast one antiperspirant or deodorant.

In one embodiment, the composition comprises an antiperspirant agent.The antiperspirant agent may be any suitable substance that reduces orinhibits the production of sweat. In some instances, an antiperspirantagent can also provide deodorancy benefits.

Preferably, the antiperspirant agent is selected from the groupconsisting of inorganic or organic salts of aluminium, zirconium, zincor mixtures thereof.

In one embodiment, the antiperspirant agent is an aluminium salt havingthe general formula:

Al₂(OH)_(x)Q_(y) ·wH₂O

where Q is chlorine, bromine or iodine;x is 2 to 5;x+y=6, where x and y do not need to be integers; andwH₂O represents a variable amount of hydration.

In another embodiment, the antiperspirant agent is a zirconium salt ofthe following general formula:

ZrO(OH)_(2n-nz)B_(z) ·wH₂O

where

z is a variable in the range of from 0.9 to 2.0 so that the value of2n-nz is zero or a positive;

n is the valency of B;

B is selected from the group consisting of chloride, other halide,sulphamate, sulphate and mixtures thereof; and

wH₂O represents a variable amount of hydration.

In a preferred embodiment, the antiperspirant agent is selected from thegroup consisting of aluminium chloride, aluminium chlorohydrate,aluminium chlorohydrex polyethylene glycol, aluminium chlorohydrexpropylene glycol, aluminium dichlorohydrate, aluminium dichlorohydrexpolyethylene glycol, aluminium dichlorohydrex propylene glycol,aluminium sesquichlorohydrate, aluminium sesquichlorohydrex polyethyleneglycol, aluminium sesquichlorohydrex propylene glycol, aluminiumzirconium octachlorohydrate, aluminium zirconium octachlorohydrex gly,aluminium zirconium pentachlorohydrate, aluminium zirconiumpentachlorohydrex gly, aluminium zirconium tetrachlorohydrate, aluminiumzirconium tetrahlorohydrex gly, aluminium zirconium trichlorohydrate andaluminium zirconium trichlorohydrex gly. These antiperspirant agentshave approved listings under the United States Food & DrugAdministration Federal Register.

It is contemplated that other antiperspirant agents may also be used.Examples of these antiperspirant agents include aluminium bromohydrate,aluminium chloride, aluminium citrate, aluminium sulfate, ammonium alum,cobalt acetylmethionate, potassium alum, sodium alum and sodiumaluminium chlorohydroxy lactate.

In another embodiment, the composition comprises a deodorant agent. Thedeodorant agent may be any suitable substance that provides deodorancybenefits in masking or neutralising odours that are produced by theaction of bacteria. Generally, deodorant agents do not interfere withthe production of perspiration. Representative examples of deodorantagents include, but are not limited to, one or more ofcetyl-trimethylammonium bromide, cetyl pyridinium chloride, benzethoniumchloride, diisobutyl phenoxy ethoxy ethyl dimethyl benzyl ammoniumchloride, sodium N-lauryl sarcosine, sodium N-palmithyl sarcosine,lauroyl satcosine, N-myristoyl glycine, potassium N-lauryl sarcosine,stearyl, trimethyl ammonium chloride, sodium aluminium chlorohydroxylactate, tricetyl methyl ammonium chloride, 2,4,4′-trichloro-2′-hydroxydiphenyl ether, diaminoalkyl amides such as L-lysine hexadecyl amide,heavy metal salts of citrate, salicylate, and piroctose, especially zincsalts, and acids thereof, heavy metal salts of pyrithione, especiallyzinc pyrithione and zinc phenolsulfate. Other deodorant agents include,without limitation, odour absorbing materials such as carbonate andbicarbonate salts, e.g. as the alkali metal carbonates and bicarbonates,ammonium and tetraalkylammonium carbonates and bicarbonates, especiallythe sodium and potassium salts, or any combination of the above

In a preferred embodiment, the composition comprises a combination ofantiperspirant and deodorant agents. The antiperspirant and deodorantagents may be present in the composition in any amount that providesbeneficial antiperspirant and/or deodorancy effects. The antiperspirantagent or deodorant agent may be present in an amount of from about 0.05to 60%, and is preferably from about 1 to 40%, more preferably fromabout 5 to 30% and even more preferably from about 8 to 15% by weight ofthe composition. Where the composition comprises a combination ofantiperspirant and deodorant agents, the combined amounts of theseagents is preferably within the preferred range stated above.

In one embodiment, the composition may comprise a penetration enhancer.The penetration enhancer is also sometimes called an “absorption”enhancer. Suitable dermal penetration enhancers are described in U.S.Pat. No. 6,299,900 and WO 2006/128255, the contents of each of which areherein incorporated by reference. The preferred dermal penetrationenhancers include: fatty acids, fatty acid esters, fatty alcohols,glycols and glycol esters, 1,3-dioxolanes and 1,3-dioxanes, macrocyclicketones containing at least 12 carbon atoms, oxazolidinones andoxazolidinone derivatives, alkyl-2-(N,N-disubstituted amino)-alkanoateesters, (N,N-disubstituted amino)-alkanol alkanoates, sunscreen estersand mixtures thereof. These include the compounds being safeskin-tolerant ester sunscreens of formula:

wherein R¹ is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy orNR³R⁴;R² is long chain alkyl;R³ and R⁴ are each independently hydrogen, lower alkyl or R³ and R⁴together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring;n is 0 or 1; andq is 1 or 2.

Most preferably the dermal penetration enhancer is selected from thelist including oleic acid, oleyl alcohol, cyclopentadecanone (CPE-218™),sorbitan monooleate, glycerol monooleate, propylene glycol monolaurate,polyethylene glycol monolaurate, 2-n-nonyl 1,3-dioxolane (SEPA™),dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) or its saltderivatives, 2-ethylhexyl 2-ethylhexanoate, isopropyl myristate,dimethyl isosorbide, 4-decyloxazolidinon-2-one (SR-38™, TCPI, Inc.),3-methyl-4-decyloxazolidinon-2-one, octyl dimethyl-para-aminobenzoate,octyl para-methoxycinnamate, octyl salicylate and mixtures thereof.

The concentration of absorption/penetration enhancer may be in the rangefrom 10-10,000 weight percent of absorption/penetration enhancer basedupon the weight of active ingredient. The ratio of penetration enhancerto active ingredient may vary considerably and will be governed as muchas anything, by the pharmacological results that are required to beachieved. In principle, it is desirable that as little absorptionenhancer as possible is used. However, it is most preferable that thepenetration enhancer be in the range from 0.01-15% of the totalcomposition.

In the most preferred embodiment of the invention the composition isformulated to dry on the skin within three minutes of application. Inthis way the composition is driven into the skin to form a reservoir ofthe physiologically active agent in the skin which we have found isparticularly active in enhancing blood levels without the undesirableeffects associated with high localised subcutaneous levels in the regionof application. Pharmacodynamically, delivery of the active issubstantially “steady-state”, once a reservoir of the active isestablished in the skin.

The composition preferably has a drying time of less than three minutes.Drying time may be determined by in vitro or in vivo tests. A suitablein vitro test involves placing a 10 μl sample on a clean glass slide atroom temperature (approx 20° C.) and using a four decimal placeanalytical balance the time take for the vehicle to stop evaporating ismeasured. The resulting drying times from three repetitions of the testmay be averaged.

For in vivo drying time measurement 10 μLs applied to volar forearms(32° C.) of three subjects and the drying time is measured by touch andvisual verification (no visible surface vehicle or shine).

Preferably the composition is non-occlusive, in that in the broadestsense, the composition is not trapped to the skin, or the skin is notclosed to the atmosphere, by means of a patch device, fixed reservoir,application chamber, tape, bandage, sticking plaster, or the like, whichremains on the skin a the site of application for a prolonged length ofterm. Such devices tend to be uncomfortable for the wearer or can beembarrassing or unsightly.

In one embodiment, the composition appears like a lotion. In thiscontext, “lotion” is used in its broad descriptive sense, rather thanthe more specific formulatory sense which refers to a mixed phase orsuspension of active. The composition is often a true solution, but withincreased viscosity so that its viscosity is more similar to thatusually associated with a lotion. The viscosity of the composition ispreferably greater than that of water but less than about 300centipoise. The viscosity in different embodiments is in the range of 10to 200, to 100 or 30 to 50 centipoise.

Without being bound by any theory, the applicant believes that theviscosity modulating agent and/or penetration enhancer in thecomposition function to minimise perspiration, and that the volatilecarrier functions to inhibit bacteria and therefore odour by abactericidal activity of the carrier.

In one embodiment, the composition consists essentially of onephysiologically active agent; one volatile solvent; and one viscositymodulating agent, each as described above. Preferably, it furtherincludes a penetration enhancer as described above. In one embodiment,the viscosity modulating agent is an antiperspirant, and the compositionoptionally also includes a deodorant. Each of these embodiments may ormay not also include water.

In another embodiment, the composition may include at least oneadditional active agent and/or at least one additional inactive agent.In a different embodiment, the composition does not include a herbalextract (or like component), whether as a physiologically active agentor otherwise.

The composition may be applied to the skin, including but not limited toaxilla, of a subject in any of a range of forms. Suitable forms includefor example lotions, creams, gels, foams, pastes, solutions, sprays,aerosols, roll-ons and the like. The composition may be applied in anocclusive or non-occlusive manner. It is preferred that the compositionis applied in a non-occlusive manner and in the most preferredembodiment the composition is formulated for application as a lotion,gel, cream, foam or viscous solution. Generally, the properties of thecomposition are such that it can be readily dispensed and spread by theimplement of the invention. The composition can be formulated by addingsuitable carriers, excipients and thixotropic agents which are inert tothe active to facilitate dispensing and spreading of the composition andthus delivery of the composition to the skin for transdermaladministration of the active agent.

The composition may further comprise additional components that willfacilitate its preparation into forms suitable for application to theaxilla of a subject. Examples of additional components include but arenot limited to surfactants, buffers, solvents and propellants.

In one embodiment, the composition comprises a volatile carrier which isisopropyl alcohol, a penetration enhancer which is octisalate, an activeagent which is testosterone and a thickening agent which ispolyvinylpyrrolidone. These may be in the following percentages:

30% v/v carrier;

8% w/v enhancer;

1% w/v active;

2% w/v thickener;

10% v/v sterile water; and

the balance ethanol.

In one embodiment, the invention utilises a transdermal drug deliverycomposition consisting essentially of the above 6 components in thoseproportions.

Other actives as set-out below are also contemplated for use in thecomposition.

In another embodiment, the composition may further include a secondactive agent to provide the composition with additional usage benefits.The second active agent may be selected from any one of the activeagents listed above, or herbal extracts and/or cosmetic agents (such as,age spot and keratose removing agents, anti-aging agents, antioxidants,and hydroxy acids).

Preferably the second active agent is an antifungal agent. Fungalinfections are common in areas of the body having higher production ofheat and perspiration.

In yet another embodiment, the composition may further comprise one ormore inactive agents. Such inactive ingredients may be referred to as“additives”. Examples of such additives include but are not limited to,humectants, deodorant agents, antiperspirants, pH adjusting agents,preservatives, emulsifiers, occlusive agents (including withoutlimitation patches and film formers), solubilizing agents, colorants,and surfactants (including without limitation anionic surfactants).

In yet another embodiment the invention provides a method of transdermaladministration of a physiologically active agent to a subject including

-   -   providing an implement as hereinbefore described;    -   applying a liquid including the physiologically active agent to        the reservoir; and    -   deforming the wall of the receptacle containing the liquid        against the skin of the subject and spreading the liquid over        the area of the skin surface preferably in at least one axilla.        The receptacle is preferably used so as to maintain the working        surface in contact with the treatment surface when spreading the        liquid.

The method can be used to deliver a predetermined amount of activeand/or sufficient active to achieve a predetermined bloodstream level orconcentration of the active. For some actives (e.g., those with a shorthalf-life) other measures of the amount of active delivered will beappropriate.

In another embodiment the invention provides use of a physiologicallyactive agent in manufacture of a medicament for treatment of a subjectby application to the skin of the subject in at least one axilla withthe above described implement. The medicament is preferably fortreatment or prevention of a condition treatable or preventable by theactive.

The invention is described with reference to the following Example. Itis to be understood that the Example is provided by way of illustrationof the invention and is not limiting to the scope of the invention.

Example

The above described implement, such as the implement of FIGS. 5 and 6may be used to apply the composition of Example 1 of WO 2006/128255 toat least one axilla of a male or female human to treat conditionsarising from deficient systemic testosterone blood levels:

The composition of Example 1 of WO 2006/128255 contained the followingcomponents in the amounts by weight specified.

Component Use Concentration Octisalate USP Penetration enhancer 8% w/vPovidone USP Thickener 1-5% Purified water USP Vehicle 10% v/v Isopropylalcohol USP Vehicle 30% v/v Alcohol USP Vehicle To 100% v/v

Various alterations, modifications and/or additions may be introducedinto the constructions and arrangement of parts previously describedwithout departing from the spirit or ambit of the invention. Morespecifically the features of any one of the embodiments may be added toother embodiments resulting in an implement that combines features ofmore than one embodiment.

1-20. (canceled)
 21. A method of transdermal administration of aphysiologically active agent from a liquid composition to a subjectincluding: providing an implement having a support, and a receptaclemounted on the support, the receptacle defining a reservoir space withan open top being configured to receive a volume of the liquidcomposition through the open top, the receptacle including a flexiblemembrane forming a base and a wall, the wall being substantiallyperpendicular to the base and having a working surface to spread theliquid composition over a treatment surface of the subject, wherein thebase has a continuous surface such that the liquid composition cannotpass through the base, wherein at least the wall is resilientlydeformable when spreading the liquid composition over the treatmentsurface; applying the liquid composition to the reservoir through theopen top; and deforming the wall of the receptacle containing the liquidcomposition against the treatment surface; and spreading the liquidcomposition over the treatment surface with the working surface of thewall.
 22. A method according to claim 21, including providing acontainer configured to contain the liquid composition, and providing adispensing device configured to deliver the liquid composition from thecontainer, and dispensing the liquid composition from the container tothe receptacle through the open top.
 23. A method according to claim 22,wherein the support is configured to detachably connect to thedispensing device, and detaching the support from the dispensing deviceso as to dispense the liquid composition from the container to thereceptacle.
 24. A method according to claim 23, wherein the dispensingdevice includes a pump and the support surrounds the pump when thesupport is attached to the dispensing device, so as to reduce thelikelihood of inadvertent discharge of the liquid composition from thepump.
 25. A method according to claim 21, wherein the implement isconfigured to be used with the treatment surface of the subject which isthe subject's skin, and spreading the liquid composition over thesubject's skin using the implement.
 26. A method according to claim 21,wherein the implement is configured to be used with the treatmentsurface of the subject which is an axilla area of the subject's skin,and spreading the liquid composition over the axilla area of thesubject's skin using the implement.
 27. A method according to claim 21,wherein the support is relatively rigid in comparison to the wall of thereceptacle, and moving the wall relative to the support when spreadingthe liquid composition over the treatment surface.
 28. A methodaccording to claim 27, wherein the wall collapses relative to thesupport when spreading the liquid composition over the treatmentsurface.
 29. A method according to claim 21, wherein the liquidcomposition includes a penetration enhancer.
 30. A method according toclaim 29, wherein the penetration enhancer is selected from the groupconsisting of fatty acids, fatty acid esters, fatty alcohols, glycolsand glycol esters, 1,3-dioxolanes and 1,3-dioxanes, macrocyclic ketonescontaining at least 12 carbon atoms, oxazolidinones and oxazolidinonederivatives, alkyl-2-(N,N-disubstituted amino)-alkanoate esters,(N,N-disubstituted amino)-alkanol alkanoates, sunscreen esters andmixtures thereof.
 31. A method according to claim 29, wherein thepenetration enhancer is one or a mixture of octyldimethyl-para-aminobenzoate, octyl para-methoxycinnamate and octylsalicylate.
 32. A method according to claim 29, wherein the liquidcomposition includes from 1 to 15% by weight of the total composition ofa penetration enhancer.
 33. A method according to claim 21, wherein theliquid composition includes from about 40-90% by weight of volatilesolvent selected from the group consisting of ethanol, ethyl acetate,isopropanol, acetone, ethyl formate, methyl acetate, methyl ethylketone, pentane, chloroform, dimethyl ether, R134a and mixtures thereof.34. A method according to claim 21, wherein the physiologically activeagent includes at least one hormone selected from the group consistingof oestrogens, progestagens and androgens.
 35. A method according toclaim 21, wherein the physiologically active agent is an androgenselected from testosterone and derivatives thereof.
 36. A methodaccording to claim 21, wherein the liquid composition comprises: (a) apharmaceutically effective amount of testosterone; (b) one or more oflower alkyl alcohols; wherein the combined amount of lower alkylalcohols is at least 60% v/v of the composition; (c) one or morepenetration enhancers; and (d) a viscosity modulating agent forincreasing the viscosity of the composition.
 37. A method according toclaim 36, wherein the testosterone is present in the liquid compositionin an amount of at least 1% w/v.
 38. A method according to claim 21,wherein the liquid composition is in the form of a lotion or gel.
 39. Amethod according to claim 21, wherein the liquid composition has aviscosity greater than water and less than 300 centipoise.
 40. A methodaccording to claim 21, wherein the subject is a male sufferinghypogonadism and the liquid composition is applied to provide a serumtestosterone level in the range of from 300 to 1000 ng/dl.